| Abstract |
[Truncated abstract] Antiretroviral therapy (ART) has improved the quality of life for human immunodeficiency virus (HIV)-infected patients by suppressing viral replication, allowing reconstitution of the immune system. However, patients initiating ART with advanced disease may experience immune restoration disease (IRD) or poor recovery of CD4+ T-cell numbers and/or functions. IRDs are attributed to immune responses that are immunopathological rather than protective. This thesis addresses possible causes of IRD and impaired CD4+ T-cell function in HIV patients who were very immunodeficient (starting ART with <200 cell/μL) but responded virologically to ART. IRD associated with tuberculosis (TB), cryptococcal meningitis, cytomegalovirus (CMV) and Varicella Zoster virus (VZV) infections were investigated. Most studies described here use patients who participated in a study of immune reconstitution after starting ART at the University of Malaya, Kuala Lumpur, Malaysia. In Chapter 3, I showed that patients who presented with IRD associated with TB or cryptococcal meningitis displayed increased interferon-gamma (IFNγ) responses to antigens from the provoking pathogens, high proportions of activated (HLA-DRhi) Tcells and high plasma levels of immunoglobulin (Ig)-G reactive to antigens. IRD was found to not associate with deficiency of CD4+ T-cells with a regulatory phenotype (CD25+CD127lo or CTLA-4+). These cells have the capacity to suppress immune responses and were observed to parallel with immune activation regardless of IRD. In Chapter 4, |
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I found no role for natural killer (NK) cells in the pathogenesis of IRD as NK cell IFNγ responses remained low in all patients starting ART. NK cell responses varied between patients with similar IRD, with no consistent peaks preceding diagnosis. However, NK cell deficiency may promote IRD by impairing the control of the provoking pathogen before ART as CD16 expression of CD56lo NK cells was low at baseline in most IRD patients. Most IRD events in the cohort were associated with Mycobacterium tuberculosis (MTB) infection, so the functions of antigen presenting cells and their Toll-like receptor (TLR)-induced responses were evaluated in patients who experienced TB IRD (Chapter 5). Evaluations of TLR2 (receptor for mycobacterium-derived lipomannan; LM) expression and LM-induced cytokine responses were included. Some patients who developed TB IRD showed increased LM-induced responses around the time of IRD diagnosis. This involved high expression of TLR2 on both myeloid dendritic cell (mDC) and monocytes followed by high tumour necrosis factor-alpha (TNFα) and interleukin (IL)-12p40 production without parallel increases in IL-10 in response to LM. Thus, inflammatory responses observed during IRD may be caused by hyper-responsive antigen-presenting cell (APC) promoting over-production of inflammatory cytokine driving downstream immune responses. CD4+ T-cell recovery (independent of IRD) was also investigated in this thesis. Malaysian patients were divided into two groups (Low vs. High) based on the attainment of more than 200 CD4+ T-cells/μL after 6 months of ART. Purified protein derivative (PPD) and cytomegalovirus (CMV)-specific IFNγ responses were similar in the two groups... |
